PURPOSE: Biologics targeting the underlying inflammation in chronic rhinosinusitis with nasal polyps (CRSwNP) not only alleviate symptoms but also provide potential disease-modifying effects. This has redefined treatment goals in CRSwNP, emphasizing the concept of achieving disease remission as proposed by the EPOS2020/EUFOREA expert panel. Remission in CRSwNP is defined as sustained control for at least 12 months, along with the absence of active disease as assessed by nasal endoscopy. The purpose of this study was to identify patients with severe CRSwNP who achieved disease remission during the first two years of Dupilumab treatment. METHODS: This real-life, observational, retrospective study evaluated the effectiveness and safety of Dupilumab in patients with severe, uncontrolled CRSwNP over two years. Remission was assessed taking into account the latest EPOS2020/EUFOREA expert panel and currently available expert opinion on the topic. Data were collected at baseline and after 1, 3, 6, 9, 12, 18, and 24 months, focusing on nasal polyp score (NPS), symptoms, olfactory function, and quality of life (QoL). Additionally, the safety profile was evaluated by monitoring side effects and eosinophil blood count. RESULTS: A total of 30 patients (19 males, 11 females; mean age 53.7 years) were included. Dupilumab treatment led to significant clinical improvements, including a reduction in NPS, relief of nasal symptoms, and notable improvements in olfactory function and QoL, as demonstrated through SNOT-22 and VAS scores. Twenty-three patients (77%) achieved disease remission. CONCLUSION: This retrospective study confirms the efficacy of Dupilumab in managing difficult-to-treat, type-2 inflammation-driven CRSwNP, with a high percentage of patients achieving remission. Further studies with larger cohorts along with universal guidelines establishing validated criteria, including specific cut-off values, for a standardized definition of remission in CRSwNP are required.